Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety and for all purposes.
Kidney disease is a serious, unmet medical condition with an annual U.S. cost burden exceeding $27 billion. Currently, more than 40 million Americans are at risk for or have kidney disease, and the incidence is increasing at an alarming rate of 6% per year. Therefore, by the year 2020, an estimated one in four people will have end-stage renal disease (ESRD), requiring either dialysis or kidney transplantation. To alleviate these economic and medical challenges, novel, transformational technologies for the treatment of both acute renal failure (ARF) and chronic kidney disease (CKD) are necessary.
Acute renal failure, also referred to as acute tubular necrosis, is a common syndrome affecting up to 7% of all hospitalized patients (Kelly et al. (2000) Semin. Nephrol. 1:4-19). ARF is the sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes. ARF most often occurs after an individual is exposed to nephrotoxic agents or following an ischemic-reperfusion event. Other causes include infection, urinary tract obstruction and some blood and autoimmune disorders. These insults induce damage to the functional component of the kidney, the nephron. More specifically, cells of the proximal tubule become necrotic. The tubule cells then detach from the tubular basement membrane, obstructing the tubular lumen. This obstruction leads to an increase in intratubular pressure, causing filtrate leakage from the nephron into the surrounding renal parenchyma. The reduction in nephron function and the accumulation of filtrate in the kidney tissue leads to a decrease in the rate of glomerular filtration, and ultimately renal failure ensues. Although ARF is a serious, life-threatening disorder, it is reversible.
Several therapeutic methods have been proposed, aimed at reducing or eliminating ARF. Most notably, advanced dialysis techniques are frequently employed. Nonetheless, the mortality rate among dialysis-treated ARF patients still remains 30-80%, indicating that dialysis has little therapeutic value in treating ARF. (Morigi et al. (2004) J. Am. Soc. Nephrol. 15:1794-804). In addition, pharmacological-based therapies such as dopamine, furosmide, mannitol or atrial natriuretic peptide administration, have failed in clinical studies (Haug et al. (1993) Transplantation 55:766-772; Lieberthal and Nigam (2000) Am. J. Physiol. Renal Physiol. 278: F1-F12). These data suggest that the traditional strategy for developing an ARF therapy is inadequate and that a new rationale must be implemented.
Recovery of renal function following ARF is dependent on the replacement of necrotic tubular cells with functional tubular epithelium. After injury, tubules are capable of self repair, forming new proximal tubular cells to replace failing or necrotic cells. The origin of the progenitor cells that give rise to new tubular cells is unknown. However, it is possible that tubular regeneration follows the stem cell/transit-amplifying cell paradigm described for more rapidly regenerating organ systems.
Recent studies have demonstrated that bone marrow-derived mesenchymal stem cells (MSCs) are renotropic and help to repair the kidneys after drug- and ischemia-induced ARF (Morigi et al. 2004). It has also been recently shown that intracarotid administration of 1×106 MSCs per rat with ischemia/reperfusion injury resulted in significantly improved renal function (Togel et al. (2005) Am. J. Physiol. Renal Physiol. 289(1):F31-42). It was further shown that the protective effects of MSCs were independent of stem cell differentiation, but rather were the result of secretion of renoprotective trophic factors.
In contrast to ARF, chronic kidney disease (CKD) is a gradual and progressive loss of kidney function. It is generally irreversible and ultimately leads to end-stage renal disease. In the United States, CKD is becoming increasingly common and is associated with poor health outcomes and high medical costs. The National Kidney Foundation estimates that 20 million Americans have CKD, and at least 20 million additional people are at risk for developing CKD. If left untreated, CKD can lead to significant morbidity and mortality from anemia, electrolyte imbalances, bone disease, cardiovascular disease, and kidney failure.
Progressive renal disease results from a combination of the initial disease injury (e.g, hypertension), followed by a maladaptive renal response to that injury. Such a response includes the production of pro-inflammatory and pro-fibrotic cytokines and growth factors. Therefore, one strategy to slow CKD progression is to ameliorate the inflammatory and fibrotic response as well as repair or reverse existing kidney damage. It has been shown that the administration of growth factors can slow CKD progression. For example, bone morphogenic protein-7 (BMP-7) prevented tubular atrophy, interstitial inflammation and fibrosis in rats with unilateral ureteric obstruction. Similarly, BMP-7 administration reduced tubulointerstitial fibrosis and glomerulosclerosis in the MRL lpr/lpr mouse model of lupus nephritis. In addition, hepatocyte growth factor has been shown to have potent anti-inflammatory and anti-fibrotic efficacy in a wide variety of animal models of kidney injury. Other factors that have shown therapeutic promise include transforming growth factor-β1, vascular endothelial growth factor (VEGF), connective tissue growth factor, fibroblast growth factor-2 (FGF-2), Interleukins, tumor necrosis factor, and monocyte chemotactic protein-1. These studies all demonstrate that the administration of growth factors is a promising therapeutic approach for the preventative treatment of CKD.
Despite existing medical treatment options, mortality rates remain very high and the incidence of kidney disease is on the rise. Therefore, a need exists in the art for an improved, potentially curative therapy. Today, no therapeutic intervention attempts to halt or even reverse kidney disease progression. The present invention provides therapeutic methods that show great renoprotective promise, and promote endogenous renal regeneration, replace necrotic renal cells and ultimately prevent ESRD.